EP2632590A1 - Microfluidic test carrier for dividing a liquid quantity into subquantities - Google Patents
Microfluidic test carrier for dividing a liquid quantity into subquantitiesInfo
- Publication number
- EP2632590A1 EP2632590A1 EP11771105.1A EP11771105A EP2632590A1 EP 2632590 A1 EP2632590 A1 EP 2632590A1 EP 11771105 A EP11771105 A EP 11771105A EP 2632590 A1 EP2632590 A1 EP 2632590A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- receiving chamber
- test carrier
- chamber
- liquid
- channel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
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- B01J4/00—Feed or outlet devices; Feed or outlet control devices
- B01J4/02—Feed or outlet devices; Feed or outlet control devices for feeding measured, i.e. prescribed quantities of reagents
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502723—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
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- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
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- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/02—Adapting objects or devices to another
- B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
- B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
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- B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L2400/06—Valves, specific forms thereof
- B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break
Definitions
- Microfluidic test carrier for splitting a quantity of liquid into sub-quantities
- the present invention relates to a microfluidic test carrier for dividing an amount of liquid in subsets.
- the test carrier comprises a substrate and a cover layer and a capillary structure enclosed by the substrate and the cover layer, which comprises a receiving chamber, a sample chamber and a connecting channel between the receiving chamber and the sample chamber.
- the receiving chamber has two opposite boundary surfaces and a side wall, wherein the one boundary surface of the bottom of the receiving chamber and the other boundary surface is the ceiling of the receiving chamber.
- Microfluidic elements for analyzing a fluid sample are used in diagnostic tests of in vitro diagnostics. In these tests, body fluid samples are assayed for one or more medical grade analytes. An important part of the analysis are test carriers on which microfluidic channel structures for the uptake and transport of a liquid sample are present Carrying out complex and multi-level test procedures ("test protocols").
- Test carriers often referred to as “lab on a CD” or “lab on a chip", consist of a carrier material, which is usually a plastic substrate. Suitable materials are, for example, COC (cyclo-olefin copolymer) or plastics such as PMMA (polymethyl methacrylate), polycarbonate or polystyrene.
- the test carriers have a channel structure which is formed in the substrate and is enclosed by a cover or a cover layer.
- the channel structure often consists of a succession of multiple channels and channel sections, as well as intervening chambers expanded in comparison to the channels and channel sections.
- the structures and dimensions of the channel structures are defined by the structuring of plastic parts of the substrate and can be achieved, for example, by injection molding.
- Microfluidic test carriers are used, inter alia, in immunochemical analyzes with a multi-stage test procedure, for.
- enzyme-linked immunosorbent assay 20 ELISA
- a separation of bound or free reaction components takes place.
- a controlled liquid transport is necessary.
- the control of the process flow can take place with internal (within the fluidic element) or with external (outside the fluidic element) measures.
- the controller can be on the
- test carriers are rotated in order to exert centrifugal forces, with which a control by changing the rotational speed, the direction of rotation or the acceleration is made.
- centrifugal forces a combination of capillary and centrifugal forces to control the
- microfluidic test elements and methods for their control are from Marc Madou, et al .; Lab on CD; Annual Review of Biomedical Engineering, 2006.8, Page 601 to 628 (online @ http: // bioenc. Annualreviews.org).
- test carriers In the case of microfluidic test carriers, several parallel partial structures are often located on a test carrier in order to be able to perform different analyzes in a single process. In order not to require the users that a sample liquid must be applied several times in small quantities, distribution structures are created in the test carriers, the liquid
- Distribution structures also ensure that the effects of sample application or sampling do not distort the validity of the result. For all analyzes the same sample material is used, e.g. in multiple determinations increases the significance.
- US 6,919,058 discloses distribution structures in which a liquid is taken up in an elongate channel which is designed in the form of a plurality of V-shaped structures arranged one behind the other.
- the distribution structure is annular on a centrifuge.
- each ventilation capillaries are provided.
- outlet capillaries are arranged, which are equipped with a hydrophobic valve.
- a pre-distribution of the liquid in the individual V-shaped structures takes place. on capillary forces. However, such a distribution is very slow.
- the test carrier is accelerated so that at some frequency the liquid breaks the hydrophobic stop and is discharged through the radially outwardly extending outlet capillaries at the base of the V-shaped structure.
- the liquid divides at the time of valve breakthrough. There is a separation of the pre-distributed part liquids.
- the derived volumes are given. If the structures are the same size, the volumes delivered from the bottom should be largely identical.
- US 4,154,793 discloses a rotating test carrier having a central receiving opening in the lid. Below the opening of the lid, a receiving space is arranged, is stored in the liquid. Around the receiving space 15, a plurality of sample chambers are peripherally arranged, which are each connected to the receiving space by a connecting channel. The inlet opening for the liquid in the sample chamber takes place at a radially outer location. For venting the sample chamber, an outlet opening is provided, which lies radially further inward than the inlet opening and
- Test carrier the liquid contained in the receiving space is emptied into the individual sample chambers, wherein the air from the sample chambers into the receiving space flows radially inward and ultimately escapes through the central opening in the lid.
- US Pat. No. 7,125,711 discloses a test carrier with an elongated distribution channel, adjoined by a plurality of measuring chambers, which are filled with capillaries. Each measuring chamber comprises a subset and has an output with a geometric valve. By rotation of the test carrier is a
- test carriers are only suitable for automated pipetting of the liquid quantities. Manual pipetting by different users,
- test carriers Air bubbles and foaming during pipetting.
- the known test carriers are not suitable for manual use.
- fabrication effects and effects in surface treatment 25 e.g., activation, hydrophilization
- test carrier with which a reliable distribution of a liquid amount can be made in predetermined subsets.
- Such a test carrier should not only be suitable for automatic pipetting and supplying the amount of liquid, but also for a manual feed through different users and should therefore be characterized by increased robustness.
- microfluidic test carrier 5 for splitting a quantity of liquid in partial quantities with the features of claim 1.
- the microfluidic test carrier has a substrate in which a capillary structure is formed.
- the capillary structure is enclosed by the substrate i o and a cover layer. It comprises a receiving chamber for receiving a sample liquid quantity, at least one sample chamber having a volume smaller than the receiving chamber, and a connecting channel extending between the receiving chamber and the sample chamber.
- 15 nal and sample chamber is used to divide the sample liquid amount into one or more subsets, which are smaller than the original amount of liquid.
- the receiving chamber has two opposite boundary surfaces
- the chamber has a circumferential venting channel and has a likewise circumferential dam, which is arranged between the interior of the receiving chamber and the venting channel.
- This dam positioned between the venting channel of the receiving chamber is arranged and designed such that it forms a geometric valve together with the venting channel.
- the geometric valve is a capillary stop for the liquid, but through which air can escape from the receiving chamber into the vent channel. The geometric valve prevents that
- the sample liquid is distributed capillary into the connected channels without an external force acting on the liquid to control liquid movement or flow.
- the dam is up, so that air can escape from the chamber.
- the venting channel has at least one outflow opening, which is in fluid communication with the connecting channel between the receiving chamber and the sample chamber and creates a connection between the outflow opening of the venting channel and an inlet opening of the sample chamber.
- the valve opens when there is enough force on the fluid. For example, this may be an external force based on acceleration or rotation.
- the geometric valve can, for. B. be overcome when reaching a certain rotational frequency of a rotating test carrier.
- the capillary stop formed by the geometric valve is designed such that an automatic fluid transport from the receiving chamber, for example by capillary forces, reliably prevented
- the receiving chamber, the venting channel and the dam are identical to The receiving chamber, the venting channel and the dam.
- the interior of the receiving chamber is located radially inward most. If one examines the test element in cross section, the arrangement of the three components from radially inward to outward takes place in such a way that the interior of the receiving chamber is arranged inside, then the circumferential dam and furthest outwardly (radially outwardly) the circulating ventilation duct. In this case, at least partial regions of the dam and the ventilation channel lie in a plane which extends parallel to the cover layer of the test element. The dam thus forms a side wall of the venting channel.
- the receiving chamber can be filled first as a distribution chamber or distribution structure. This is preferably done with a resting microfluidic test carrier.
- the robustness of the system is increased by the round configuration of the receiving chamber and preferably by a smallest possible surface-volume ratio of the receiving chamber. capillary Lar practice and the surface structure or surface treatments have only a negligible impact on the robustness of the distribution system.
- the surface-to-volume ratio of the chamber in which the chamber is preferably as high as possible, a distribution of the liquid which is as even as possible can be achieved even when the distribution is initially uneven. A pre-distribution based on capillary forces, as is usual in the prior art, is not necessary.
- the quality of the distribution volumes and the uniformity of the individual partial volumes is independent of the sample application. Thus, a high sample application speed can be achieved.
- a liquid sample can flow very quickly into the chamber.
- Such receiving chambers are particularly suitable for manual pipetting.
- the geometric valve extending at least partially or circumferentially along the circumference of the receiving chamber ensures that the distribution of the sample in the receiving chamber does not affect the quality of the distribution volumes as compared to the prior art systems described above. Only through the action of an additional force to
- the geometric valve is overcome and liquid is led out of the receiving chamber.
- the filling of the receiving chamber is independent of the distribution of the total amount of liquid to subsets. Filling and distributing to sub-volumes are completely decoupled.
- the splitting of the liquid is not carried out by capillary forces, but by a control force such.
- the problems associated with capillary force distribution of the fluid are avoided. Air bubbles are due to their lower density in the
- test carrier therefore makes it possible to divide a sample liquid which is disturbing is unaffordable and stable and has no dependencies on any contamination in distribution structures or dependencies on the surface finish of the distribution structures.
- the microfluidic test carrier is a rotating disc, such as a compact disc (CD) -like disc, and rotates about an axis of rotation that preferably extends through the test carrier.
- the test carrier is designed such that the axis of rotation extends through the center or the center of gravity of the test carrier.
- the inventive design of the receiving chamber allows a very fast recording of the sample. Since significantly different pipetting rates are to be expected in practice, in particular in the case of manual filling by the user, this ensures that there is no overflowing of the sample port in any case. Overflowing would result in contamination of the test carrier surface and may result in contamination of the device, especially with rotating test carriers. Moreover, with small volumes and slow pipetting
- the receiving chamber is designed such that the smallest possible surface-volume ratio arises.
- the receiving chamber would be spherical, since the lowest surface-to-volume ratio exists here.
- the surface-to-volume ratio is 0.9 mm 2 / mm 3 .
- the surface-volume ratio of the receiving chamber should have a value of at most 2.5 mm 2 / mm 3 , preferably at most 2 mm 2 / mm 3 .
- One of the boundary surfaces of the receiving chamber has an inlet port for externally adding a liquid sample.
- the inlet port is arranged in the ceiling of the receiving chamber. This allows the user to add the liquid sample from above. If the cover of the test carrier, at least in the region of the receiving chamber, made of a transparent material, so the user can observe the filling of the receiving chamber. There is an optical feedback to the user during filling instead.
- the curved boundary surface of the receiving chamber is the ceiling.
- the curved boundary surface forms the floor.
- the floor is curved in such a way that it rises towards the edge of the receiving chamber.
- microfluidic test carrier with a capillary structure which has a receiving chamber, at least one sample chamber and a connecting channel arranged between the chambers, two types of distribution of the liquid quantity in partial quantities can be realized. On the one hand, there is a parallel distribution over several sample chambers possible; on the other hand, a serial distribution of the total liquid sample quantity on several chambers.
- the venting channel preferably has a plurality of outflow openings, which in each case are in fluid communication with a connection channel which extends from the receiving chamber to a respective sample chamber.
- the outflow openings are distributed equidistantly on the venting channel, so that there is an even distribution along the circumference of the venting duct.
- the individual sample chambers can have the same or different volumes, so that the total liquid quantity can be distributed to the same or different partial volumes. With equal volumes of the sample chambers, there is an (absolutely) uniform distribution of the liquid,
- the venting channel has only one outflow opening (outlet port), so that a liquid contained in the receiving channel flows through the outflow opening and the adjoining connecting channel into a first sample chamber.
- the first sample chamber is connected by an outlet channel to at least one further chamber, so that liquid can flow from the sample chamber into the outlet channel through an outlet opening of the sample chamber.
- this chamber may also be a sample chamber.
- this further fluid chamber is a waste chamber (waste chamber) in which excess fluid is collected. In this way, the total sample volume can be on
- FIG. 1 shows a schematic diagram of a microfluidic test carrier and three
- Figure 2 is a detail view of a receiving chamber from the test carrier of Figure 1;
- Figure 3a, b shows two cross sections through the test carrier of Figure 1;
- Figure 4a-c each a partial view of the test carrier of Figure 1 to illustrate the filling and dispensing;
- FIG. 5 shows an alternative embodiment of a test carrier for the parallel distribution of a liquid sample over a plurality of sample chambers
- Figure 7 is a section through the receiving chamber of Figure 6;
- Figure 8 is a perspective drawing of the receiving chamber
- FIG. 9 is a perspective sectional view of the receiving chamber of Figure 6;
- FIG. 10 shows a schematic diagram for filling and distributing a liquid in the test carrier from FIG. 5.
- FIGS. 1 to 10 show embodiments of a microfluidic test carrier 1 according to the invention, which comprises a line system 2 with a capillary channel structure 3.
- the channel structure 3 is formed in a substrate 4 made of plastic.
- the capillary structure 3 is preferably produced from the substrate by injection molding or by material-removing methods.
- the test carrier 1 further comprises a cover layer, not shown in FIG. 1, which rests on the substrate 4 such that the channel structure 3 is enclosed by the substrate 4 and the cover layer.
- the test carrier 1 is a rotating test carrier 1, which rotates about an axis of rotation 5.
- the test carrier 1 is in the form of a thin disk, for example in the form of a CD. It is held in a rotating device having a rotating shaft which is aligned with the rotation axis 5.
- the axis of rotation 5 extends through the test carrier 1, preferably through
- the capillary structure 3 comprises a receiving chamber 6 with an inlet port 7, through which a liquid sample or a quantity of liquid can be introduced into the receiving chamber 6.
- the liquid sample 25 is added, for example, by manual or automated pipetting.
- the receiving chamber 6 shown here by way of example has a volume of 160 ⁇ .
- the surface to volume ratio is about 1.8 mm 2 / mm 3 and is thus below the preferred value of 2.5 mm 2 / mm 3 or 2.0 mm 2 / mm 3 .
- Pipetting can also be done manually.
- the channel structure 3 also comprises at least one sample chamber 8 and a connecting channel 9 which extends between the receiving chamber 6 and the Sampling chamber 8 extends and establishes a fluid connection between the two chambers 6, 8.
- the connecting channel 9 is formed as a relatively short channel.
- the connecting channel 9 has a length between
- the length of the connecting channel 9 is equal to 2.7 mm.
- Cross section of this channel is preferably in the range between 0.01 mm 2 to 0.25 mm 2 . Typical values are for example 0.09 mm 2 .
- the channel shown here has a width of 0.2 mm and a height of 0.15 mm. Its cross section is therefore 0.03 mm 2 .
- the dimension of the connecting duct 9 has an influence on the complete emptying of the receiving chamber, which should preferably take place much more slowly than a uniform distribution of the liquid in the receiving chamber 6.
- the duration of the complete emptying of the receiving chamber 6 is about six times greater than the duration for a uniform distribution of the liquid.
- FIGS. 1-4 show an exemplary embodiment of the test carrier 1 with a capillary structure 3 with three sample chambers 8, 10, 11.
- sample chambers 8, 10, 1 1 are connected in series (serially) and each connected by a channel 12.
- I I form a fluidic series connection or series circuit, so that a liquid from the receiving chamber 6 first in the sample chamber 8 and from there into the sample chamber 10 and then into the sample chamber 1 1
- Another chamber 13 connects, which is designed as a waste chamber 14 and forms a fluid waste reservoir for excess liquid.
- the volumes of all sample chambers 8, 10, 11 and the waste chamber 14 together are preferably approximately as large as the volume of the receiving chamber 6, preferably somewhat larger.
- the total of three sample chambers 8, 10, 11, make it possible to divide the volume of liquid introduced into the receiving chamber 6 into a total of three subsets which, due to the geometry of the sample chambers 8, 10, 1 1 are determined.
- several sample chambers can be used.
- An embodiment with two sample chambers is also conceivable.
- the fluidically serially arranged sample chambers 8, 10, 1 1 allow a division of a (small) volume of a liquid, which is less than the total volume of the three sample chambers. With a smaller volume, a liquid is divided into only one or two chambers, since the sample chambers 8, 10, 1 1 fill one after the other and a subsequent sample chamber 10 is filled only when the preceding sample chamber 8 is completely filled.
- a liquid is divided into only one or two chambers, since the sample chambers 8, 10, 1 1 fill one after the other and a subsequent sample chamber 10 is filled only when the preceding sample chamber 8 is completely filled.
- test carrier should be marketed as a single-parameter or multi-parameter test carrier.
- This type of sample distribution also offers great advantages for the customer, as only 1/3 is needed for the analysis of a parameter or 2/3 of the sample volume for the analysis of two parameters.
- the same test carrier can be used in each case.
- the receiving chamber 6 is preferably arranged on the test carrier 1 such that the axis of rotation 5 extends through the receiving chamber 6.
- the axis of rotation extends through the inlet port 7, preferably through the center of the inlet port 7 of the receiving chamber 6.
- receiving chamber 6 may be arranged in the test carrier 1 such that the axis of rotation 5 extends through the center or the center of gravity of the receiving chamber 6.
- the receiving chamber 6 is arranged eccentrically to the center of the test carrier 1 or to its center of gravity. The center of the here run
- Test carrier 1 The rotation axis 5 thus does not extend through the center of the receiving chamber 6.
- the eccentric to the receiving chamber 6 arranged inlet port 7 is arranged concentrically to the axis of rotation 5.
- Figure 2 shows a detailed drawing of the receiving chamber 6 in a view of the underside.
- the inlet port 7 is arranged centrally in the test carrier 1 and eccentrically to the center of the receiving chamber 6.
- the receiving chamber 6 has a circumferential channel 15, which is a vent channel 16 5.
- a dam 18 is formed which extends concentrically to the venting channel 16.
- the dam 18 and the venting channel 16 are at least partially disposed in a plane whose surface normal extends parallel to the axis of rotation.
- the vent passage 16 has a radially inner side wall formed by the dam 18, a radially outer side wall 27 which is the outer wall of the receiving chamber 6, and a bottom which is disposed substantially parallel to the cover layer 21 of the test element.
- the vent passage 16 may have a constant width and a constant height over its entire circumference. He
- 15 may also have circumferentially varying dimensions, but preferably at least its height is constant.
- the vent 16 and / or the dam 18 may be partially or partially interrupted.
- the dam 18 may be interrupted in several sections in such a way that it extends up to the ceiling of the building.
- the dam and / or the venting channel preferably extends over at least 50% of the circumference of the receiving chamber 6, preferably over at least 80% of the circumference and more preferably over at least 90% of the chamber circumference. With the venting channel 16 or dam 18 interrupted, however, it must be ensured that the geometric valve function formed by them remains intact.
- the dam 18 is formed by a wall 19 which has a thickness (dimension in the radial direction) which preferably corresponds to the width of the subsequent separation.
- FIG. 30 ventilation duct 16 corresponds.
- the height of the wall 19 is less than the height of the (radially outer) side wall 27 of the vent channel 16, so that between the cover layer 21 of the test carrier 1 and the top 20 of the wall 19, a gap 29 is formed.
- the gap height is less than the height of the venting channel 16.
- Figures 3a and 3b each show a section through the test carrier 1.
- the receiving chamber 6 has two boundary surfaces 22, 23.
- the boundary surface 22 is the bottom 24 of the receiving chamber 6, the opposite 5 limiting boundary surface 23 is the ceiling 25.
- the bottom 24 is formed by the substrate 4.
- the boundary surface 23 is formed by the cover layer 21, which rests on the substrate 4 of the test carrier 1.
- the cover 25 is formed by the substrate 4, while the base 24 is the cover layer 21 contacting the substrate 4.
- one of the boundary surfaces 22, 23 of the receiving chamber 6 is curved.
- the cover 25 formed by the substrate 4 is curved.
- the bottom 24 15 forming boundary surface 22 is flat.
- the ceiling 25 has the funnel-shaped inlet port 7, through which the amount of liquid to be divided is placed in the receiving chamber 6.
- FIG. 3 a shows an embodiment in which the bottom 24 is curved
- the plane cover layer 21 forms the
- Ceiling 25 and has the inlet port 7. If the cover layer 21 as a cover 25 is a transparent film, then, with manual pipetting of a liquid, good visual feedback can take place via the volume already metered into the receiving chamber 6. If the inlet port 7 is formed in the substrate 4, then visual feedback is likewise possible if the substrate is transparent, at least in the region of the receiving chamber.
- the curved design of a boundary surface 22, 23 has the advantage that air entering either at a curvature of the ceiling 25 to
- the venting channel 16 has exactly one outflow opening 26. It is preferably arranged at the location of the venting channel side wall 27, which is the furthest away from the axis of rotation 5 in the case of an eccentrically arranged receiving chamber 6. In the illustrated embodiment, where the axis of rotation 5 is concentric with the circular inlet port 7, the distance between the outlet port 26 and the inlet port 7 is the largest distance present in the chamber 6. Upon rotation of the test carrier 1 io, the liquid is forced radially outward and collects anyway in the area around the discharge opening 26. It is thus ensured that the entire liquid exits from the receiving chamber 6, since the last remainder to the discharge opening 26 is pressed.
- the dam 18 and the venting channel 16 together form a geometric valve 28. Liquid, which is to flow from the receiving chamber 6 into the sample chamber 8, must flow through the valve 28, ie via the dam 18 and through the venting channel 16, to pass through to get the connection channel 9 in the sample chamber 8. The between the top 20 of the
- Capillary gap 29 formed between dams 18 and opposite boundary surface 22 is less than the height of the subsequent venting channel 16.
- capillary gap 29 is formed between top 20 and bottom 24, as shown in FIG. 3a.
- the receiving chamber 6 can be completely or partially filled with the sample liquid or liquid to be distributed.
- Figure 4a shows a partial filling of the receiving chamber 6, while Figure 4b represents a complete filling. Trapped in the receiving chamber 6 air 60 can pass through the geometric valve 28 and escape through the vent passage 16 in the subsequent connection channel 9, until it escapes into the environment from one of the vent openings 32 of the following sample chambers 8, 10, 11 (cf., FIG. 1).
- the geometric valve 28 opens. Liquid flows out of the receiving chamber 6 radially outwards into the venting channel 16. From this, the liquid passes the outflow opening 26 in the connecting channel 9, which has another optional geo io metric valve 30 in the example shown. Also, this geometric valve 30 is opened by the centrifugal force, so that liquid flows into the first sample chamber 8, Fig. 4c.
- the pressure built up by the centrifugal force of the liquid when leaving the receiving chamber 6 is significantly greater than the flow resistance.
- the receiving chamber 6 is therefore completely emptied, with excess liquid from the last sample chamber 1 1 flows into the adjoining waste chamber 14.
- the serial arrangement of the three sample chambers 8, 10, 1 1 makes it possible not only to distribute the total volume formed by the three chambers. It is also possible to fill the receiving chamber 6 only with an amount of liquid to 5, which corresponds to the volume of the two sample chambers 8 and 10 and the connecting channel 9 and the outlet channel 34. In this case, a distribution or aliquoting of the amount of liquid takes place on only two sample chambers 8, 10.
- the volume of a sample chamber and the (essentially negligible) volume of the connecting channel 9 forms the minimum volume for the filling of the receiving chamber 6.
- the receiving chamber 6 significantly larger than the total volume of the three sample chambers 8, 10, 1 first This allows the end user to work largely undosed. In other words, it does not matter whether the minimum amount required by the three sample chambers 8, 10, 11, or the maximum amount which the receiving chamber 6 accommodates.
- the volume of each of the three identical sample chambers 8, 10, 1 1 each 30 ⁇ .
- the total capacity of the receiving chamber 6 is 160 ⁇ . If the receiving chamber 6 filled with more liquid than the three 25 sample chambers 8, 10, 1 1 hold, the excess liquid is received in the waste chamber 14
- test carrier 1 according to the invention has the advantage that the filling of the distribution structure formed by the receiving chamber 6 by the geometric
- valve 28 is completely decoupled from the distribution or distribution of the liquid (aliquoting).
- a temporal limitation during sample application ie when filling the receiving chamber 6, for example by the customer, does not exist.
- Two or more further chambers optionally adjoin the receiving chamber 6, wherein chambers can in turn connect to these in order, for example, to allow a parallel reaction.
- These chambers may be separation chambers for separating liquid and cellular sample components, reagent chambers for dissolving a reagent, mixing chambers, waste chambers or other chambers.
- FIGS. 5 to 10 show by way of example an alternative embodiment of a test carrier 1 according to the invention with a fluidic parallel connection of, for example, three sample chambers 8, 10, 11 instead of the series connection of the sample chamber 8, 10, 11 according to the embodiment according to FIGS 4.
- two or more sample chambers may be formed. The following are the main differences:
- a central receiving chamber 6 is also arranged, whose center or center of gravity is preferably identical to the center or center of gravity of the test carrier 1.
- the axis of rotation 5 is also arranged, whose center or center of gravity is preferably identical to the center or center of gravity of the test carrier 1.
- the inlet port 7 of the receiving chamber 6 is also concentric with the axis of rotation. 5
- each of the sample chambers 8, 10, 1 1 has a connecting channel 9 to the receiving chamber 6, which in each case is obtained from an outflow opening 26 of the venting channel 16 to an inlet opening 35 of the sample chamber 8, 10, 11. stretches.
- the connecting channel 9 is S-shaped in this embodiment and significantly longer than the connecting channel 9 in the serial arrangement, as shown in Figures 1 to 4. Of course, a short, radially outwardly extending 5 connecting channel 9 could also be used in this parallel arrangement. An S-shaped channel 9 could also be used in the serial configuration.
- the length of the long connection channel in this example is typically at least 7 mm.
- the length is preferably at least 9 mm, in particular preferably at least 10 mm.
- the S-shaped configuration of the elongated channel has the advantage that space is saved in the radial direction. In addition, it allows the smallest possible radius in the transition into the sample chambers and thus the lowest possible centrifugal force at this point. This has a positive effect on the emptying speed
- the cross section should preferably be between 0.01 and 0.25 mm 2 .
- the connecting channel 9 at the outflow opening 26 has a cross section of 0.09
- the connecting channel 9 is tapered and has a width of 0.2 mm and a height of 0.15 mm. Its cross section is therefore 0.03 mm 2 . With such a connecting channel, it is possible, the discharge duration, the complete emptying of the receiving chamber. 6
- the 25 is required to make about three to four times longer than the duration for a uniform distribution of the liquid in the receiving chamber 6, which is also referred to as leveling.
- the duration for a leveling is 1.5 sec, as in the case of the serial configuration. The complete emptying takes place with parallel execution
- the vent channel 16 forms with the circumferential, radially inner dam 18, a geometric valve 28, which is an independent outflow of liquid, for. B. prevents blood. Only when the valve 30 opens, the liquid can flow into the sample chambers 8, 10, 1 1.
- the gap 29 between the upper side 20 and the cover layer 21 is less than the height of the adjoining ventilation channel 16.
- the sample chambers 8, 10, 11 preferably each have an outlet opening 33, through which liquid from the sample chamber 8, 10, 11 can flow into the outlet channel 34.
- a further fluid chamber 13 is arranged with an inlet opening 39, which is in fluid communication with the sample chamber 8, 10, 1 1.
- the fluid chamber 13 is preferably a waste compartment (waste chamber) 14 and receives excess fluid.
- the sample chambers 8, 10, 1 1 each have a volume of 30 ⁇ , the receiving chamber 6 has a volume of 160 ⁇ .
- the volume of liquid from the receiving chamber 6 is evenly distributed to the sample chambers 8, 10, 1 1, wherein the remaining liquid flows into the respective waste chamber 14.
- the receiving chamber 6 can be filled both with the minimum filling amount, which corresponds to the sum of all connecting channels 9 and sample chambers 8, 10, 1 1, and also completely, which corresponds to the maximum filling quantity. This ensures that the complete volume of the receiving chamber
- the receiving chamber 6 can be filled with any, lying between minimum and maximum filling amount of liquid. This results in a wide liquid range for a liquid analysis, z. B. of blood or other body fluid. This can improve pipetting and adding liquid to the user, especially during manual pipetting, and facilitate handling.
- the venting channel 16 has a plurality of outflow openings 26, which are in fluid communication with a respective connecting channel 9.
- the outflow openings 26 are equidistant, ie evenly distributed over the circumference of the venting channel 16.
- the venting channel 16 extends over the entire circumference of the receiving chamber. 6 This applies to the channel 16 in all embodiments according to Figures 1 to 10.
- the dam 18 and / or the venting channel 16 are interrupted in sections.
- the interruption of the ventilation channel 16 is preferably not in the region of the outflow openings 26.
- the flow resistance of the distribution capillary formed by the connecting channels 9 can be used as a control instrument.
- the liquid sample i. H. she has no time to evenly distribute in the receiving chamber, resulting in uneven volumes.
- the integration according to the invention of long channels with a small cross section which act as a flow brake over their length and slow down the distribution process, improves the uniform distribution into many subsegments without the need for uniform capillary pre-distribution.
- the integration of the connection channels allows aliquoting (distribution) at high frequencies (good controllability) and at the same time
- Centrifugation starts and, due to the flow resistance in the connection channels between the receiving and the sample chamber, a uniform distribution of the liquid in the receiving chamber can be formed (without the liquid breaking through the sample chambers uncontrolled).
- the liquid is distributed in such a way that it flows towards the edge of the chamber and rests on the edge of the chamber, while in the middle of the chamber the air of the chamber is positioned (see Fig. 10c). This forming in the middle of the chamber air is known in professional circles as meniscus.
- the meniscus itself
- the distribution of the liquid in the test carrier according to the invention is independent of 5 the position of the liquid sample in the receiving chamber.
- the inventive design of the channel structure therefore allows a very precise distribution of the amount of liquid and avoids the occurring in the prior art inaccuracies.
- the parallel formed capillary structure 3 allows a simultaneous distribution of the liquid quantity to the individual sample chambers 8, 10, 1. In particular, in in vitro analyzes and investigations of blood as a liquid, the simultaneous distribution ensures that the same hematocrit values and the same lipemic portions of the erythrocytes lead to plasma ratios in all
- FIG. 7 shows that the cover 25 is formed by the flat covering layer 21 and has the round inlet port 7.
- the circumferential dam 18 and the circumferential venting channel 16 are arranged in this case near the cover layer 21. she
- the curved bottom 24 of the receiving chamber 6 preferably rises towards the dam 18. In the receiving chamber 6 incoming liquid is directed at standstill of the test carrier 1 by the resulting capillary specifically radially outward.
- the liquid transport in the receiving chamber 6 is preferably supported by a (central) elevation 40 on the bottom 24.
- the survey is cone-shaped, as can be seen in Figures 6 to 9.
- the cone-shaped elevation 40 is preferably a cone 41 and is preferably
- the conical projection 40 may also be formed as a truncated cone.
- the survey in a very different form, for example in the form of a hemisphere o. ⁇ ., Be formed.
- the cone 41 ensures that the blood is held in the middle by adhesion.
- the remainder of the sample flows in the direction of the circumferential dam 18 into the environment of the cone 41, which is reinforced by cohesion.
- the cone 41 thus represents during the pipetting a flow brake in the inlet port 7, which generates a normalization of the pipetting speed to a certain extent.
- the cone 41 causes equalization of different examinations and supports the robustness of the examination system.
- the bottom 24 of the receiving chamber 15 6 is curved such that formed in a collecting region 42 near the discharge opening 26 is a trough 43, flows into the liquid and is collected.
- a depression 43 is formed in front of each outflow opening 26.
- the receiving chamber 6 has three collection areas 42 and three wells 43rd
- the curvature is preferably such that the height at the inlet port 7 is greatest. As a result, the liquid flows outward and is directed towards the outside from the middle of the chamber (liquid wants to remain in the middle, but capillary action increases towards the outside).
- the receiving chamber 6 of the test carrier 1 has a lateral bulge 44.
- a bulge 44 directed radially outwards is arranged in each collecting region 42.
- the receiving chamber 6 is in its side wall, which is formed by the venting channel side wall 27 det 5, extending from the center of the receiving chamber 6 wegersharend away.
- the receiving chamber 6 has in this example three radially outwardly extending bulges 44, in each of which the outflow openings 26 are arranged, to which the connection channels 9 connect to the sample chambers 8, 10, 1 1. As soon as the test carrier 1 is set in rotation, the liquid is pressed into the bulges 44 and thus directed directly to the outflow openings 26.
- the receiving chamber has in each case a groove 45 in the bottom 24, which extends radially outward.
- the groove 45 extends from the foot of the cone 41 to the bulge 44.
- the groove 45 has the function of receiving a hydrophilizing solution during the manufacturing process in order to hydrophilize the receiving chamber 6, which consists of a substrate 4 made of hydrophobic plastic.
- FIG. 10 a shows that when the receiving chamber 6 is partially filled, an air bubble 60 can initially form, which is arranged here in front of an outflow opening 26. The air can pass through the venting channel 16 and one of the outflow openings arranged there. escape 26. A filling of the chamber until full filling remains possible ( Figure 10b).
- FIG. 10 c shows a partial emptying of the receiving chamber 6 after the test carrier 1 has been set in rotation and the rotational frequency (rotational speed) is above the breakdown frequency of the valve 28 formed by the dam 18 and the venting channel 16. From this rotational speed, the valve 28 opens and liquid flows uniformly through the outflow openings 26 into the connected connection channels 9. The liquid is pressed into the recesses 44 and into the recesses 43 arranged in the collection areas 42. If the receiving chamber 6 is further emptied, a separation of the individual collecting regions 42 or of the liquid collected in the individual collecting regions 42 takes place. The separation is supported by the ridges 46 (burr) and the bulge 44. On
- the separation of the amount of liquid in the receiving chamber 6 is particularly advantageous if the connecting channels 9 a different
- Recording chamber 6 would otherwise absorb a liquid channel 9 with a larger cross-section more liquid and drain faster. This is prevented by dividing the liquid into first partial volumes. The separate liquid subsets can only flow out of the associated 25 outflow openings 26. No liquid can flow from a trough 43 into an adjacent trough 43.
- the circumferential dam 18 in the receiving chamber 6 in particular by the design of the gap 29, the speed at which the liquid from the receiving chamber 6 flows out, are set.
- the liquid flows out of the receiving chamber 6 so slowly that air bubbles in the receiving chamber 6 can be displaced out of the liquid even at high rotational speeds and do not cause any volume errors. This is true even if the air bubbles are pipetted in the liquid sample.
- Forming foam can also lead to no volume error in the distribution of the amount of liquid because it is evenly displaced by its low density into the interior of the chamber to the inlet port.
Abstract
Description
Claims
Priority Applications (1)
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EP11771105.1A EP2632590B1 (en) | 2010-10-28 | 2011-10-13 | Microfluidic test carrier for dividing a liquid quantity into subquantities |
Applications Claiming Priority (3)
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EP10189261A EP2486978A1 (en) | 2010-10-28 | 2010-10-28 | Microfluid test carrier for separating a fluid volume in partial volumes |
PCT/EP2011/067929 WO2012055707A1 (en) | 2010-10-28 | 2011-10-13 | Microfluidic test carrier for dividing a liquid quantity into subquantities |
EP11771105.1A EP2632590B1 (en) | 2010-10-28 | 2011-10-13 | Microfluidic test carrier for dividing a liquid quantity into subquantities |
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EP2632590A1 true EP2632590A1 (en) | 2013-09-04 |
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EP11771105.1A Active EP2632590B1 (en) | 2010-10-28 | 2011-10-13 | Microfluidic test carrier for dividing a liquid quantity into subquantities |
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EP (2) | EP2486978A1 (en) |
JP (1) | JP5908917B2 (en) |
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CN101850231B (en) * | 2009-07-03 | 2012-08-29 | 中国科学院上海微系统与信息技术研究所 | Micro-fluid reactor, using method and application thereof |
-
2010
- 2010-10-28 EP EP10189261A patent/EP2486978A1/en not_active Withdrawn
-
2011
- 2011-10-13 EP EP11771105.1A patent/EP2632590B1/en active Active
- 2011-10-13 CN CN201180052524.XA patent/CN103167911B/en active Active
- 2011-10-13 WO PCT/EP2011/067929 patent/WO2012055707A1/en active Application Filing
- 2011-10-13 KR KR20137010846A patent/KR101495563B1/en active IP Right Grant
- 2011-10-13 JP JP2013535352A patent/JP5908917B2/en active Active
-
2013
- 2013-04-26 US US13/871,720 patent/US9186671B2/en active Active
- 2013-08-15 HK HK13109544.7A patent/HK1182048A1/en not_active IP Right Cessation
Non-Patent Citations (1)
Title |
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See references of WO2012055707A1 * |
Also Published As
Publication number | Publication date |
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KR20130099122A (en) | 2013-09-05 |
JP2013541013A (en) | 2013-11-07 |
US9186671B2 (en) | 2015-11-17 |
KR101495563B1 (en) | 2015-02-25 |
CN103167911A (en) | 2013-06-19 |
EP2486978A1 (en) | 2012-08-15 |
US20130236376A1 (en) | 2013-09-12 |
JP5908917B2 (en) | 2016-04-26 |
WO2012055707A1 (en) | 2012-05-03 |
HK1182048A1 (en) | 2013-11-22 |
EP2632590B1 (en) | 2020-03-04 |
CN103167911B (en) | 2015-08-19 |
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